1. Field of the Invention
The present invention relates to a compound having a novel morpholinopurine derivative structure that inhibits phosphatidylinositol 3-kinase (PI3K) and/or the mammalian target of rapamycin (mTOR).
2. Description of the Related Art
PI3K is a lipid kinase known to play an important role in cellular growth, survival, motion, and the like. Class I PI3Ks (PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ) are known to be activated by a receptor tyrosine kinase or GPCR to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) to activate Akt. It has been reported that the activated Akt regulates cellular growth, survival, angiogenesis, and the like by phosphorylating TSC2, GSK3β, MDM2, FOXO, BAD, and the like (Non-Patent Document 1).
p110α, a catalytic subunit of PI3Kα, is known to be activated in colon cancer, breast cancer, brain tumor, gastric cancer, liver cancer, ovary cancer, and the like due to mutation thereof. Furthermore, it is known that the PI3K-Akt pathway is also activated in cancers in which PTEN (phosphate and tensin homolog), which dephosphohrylates PIP3, is inactivated (for example, prostate cancer and melanoma) and cancers in which p110α is overexpressed (for example, ovary cancer and lung cancer). Therefore, it is suggested that a drug which exhibits PI3K inhibitory effect can inhibit cancer cell growth and survival, angiogenesis, and the like by suppressing the activation of Akt to block the PI3K-Akt pathway, and its usefulness as a cancer therapeutic agent is expected (Non-Patent Documents 2 and 3).
Compounds having PI3K inhibitory activity that have been reported include pyridinylfuranopyrimidine derivatives (Non-Patent Document 4 and Patent Document 1), thienopyrimidine derivatives, and furopyrimidine derivatives (Patent Documents 2 to 5), pyrimidine derivatives (Patent Documents 6 to 15), pyridopyrimidinone derivatives (Patent Documents 16 and 17), and imidazoquinoline derivatives (Non-Patent Document 5 and Patent Document 18). A compound having a hydrogen atom at Ra and at the 8th position of the purine ring and a 3-hydroxyphenyl group at the 2nd position in the general formula (I) described later has been reported as a PI3K inhibitor (Patent Document 19).
The mammalian target of rapamycin (mTOR) is a serine-threonine kinase activated by a signal from a growth factor (for example, insulin) via the PI3K-Akt pathway (Non-Patent Document 6). It is thought that mTOR activates translation of mRNA and the like by phosphorylating S6K1 and 4E-BP1 and promotes syntheses of proteins involved in cell growth, angiogenesis, and the like (for example, c-myc, cyclin D1, and HIF-1α).
Rapamycin, a macrolide antibacterial agent, is known to inhibit the kinase activity of mTOR by forming a complex with FKBP12 and mTOR in the cell. Currently, clinical studies of rapamycin derivatives, such as CCI-779, as anti-cancer agents are ongoing.
Meanwhile, it has recently been revealed that some mTOR kinase activities are not inhibited by rapamycin (for example, the activity of phosphorylating Akt). It has been reported that mTOR forms at least two complexes, specifically, rapamycin-susceptible mTOR Complex 1 (mTORC1) (complex containing raptor and the like) and rapamycin-non-susceptible mTOR complex 2 (mTORC2) (complex containing rector and the like). Since a drug that exhibits inhibitory effect on mTOR kinase can inhibit both mTORC1 and mTORC2, it is expected to have broader therapeutic effect as an anti-cancer agent than rapamycin (Non-Patent Document 7).
As compounds having mTOR inhibitory activity, pyridopyrimidine derivatives (Patent Document 20), imidazopyrazine derivatives (Patent Document 21), and the like have been reported.
As compounds that inhibit both PI3K and mTOR, imidazolopyrimidine derivatives (Patent Document 22), 2-morpholinopurine derivatives (Patent Document 23) and 2-morpholinopurine derivatives substituted with pyrimidine moiety at 6-position (Patent Document 24) have been reported.
As compounds that inhibit PI3Kδ more selectively than other subtypes of PI3K, morpholinopurine derivatives substituted with indole moiety at 2-position have been reported (Patent Document 25).    Patent Document 1: Japanese Patent Laid-Open No. 2005/120102    Patent Document 2: WO2008/070740    Patent Document 3: WO2007/127183    Patent Document 4: WO2007/129161    Patent Document 5: WO2007/122410    Patent Document 6: WO2007/084786    Patent Document 7: WO2008/098058    Patent Document 8: WO2008/032072    Patent Document 9: WO2008/032060    Patent Document 10: WO2008/032036    Patent Document 11: WO2008/032033    Patent Document 12: WO2008/032089    Patent Document 13: WO2008/032091    Patent Document 14: WO2008/032086    Patent Document 15: WO2008/032028    Patent Document 16: WO2007/044698    Patent Document 17: WO2007/044813    Patent Document 18: WO2006/122806    Patent Document 19: GB2431156    Patent Document 20: WO2008/023161    Patent Document 21: WO2008/051493    Patent Document 22: U.S. Patent application publication No. 2008/0233127    Patent Document 23: WO2009/045174    Patent Document 24: WO2009/045175    Patent Document 25: WO2009/053716    Non-Patent Document 1: Nature Rev. Cancer, 5, 921-929 (2005)    Non-Patent Document 2: Nature, 441, 366-370 (2006)    Non-Patent Document 3: Nature Rev. Genet., 7, 606-619 (2006)    Non-Patent Document 4: Cell, 125, 733-747 (2006)    Non-Patent Document 5: Mol. Cancer Ther., 7(7), 1851-1863 (2008)    Non-Patent Document 6: Cancer Cell, 12(1), 9-22 (2007)    Non-Patent Document 7: Drug Discov. Today, 12(3-4), 112-124 (2007)
An object of the present invention is to provide a novel orally bioavailable low molecular compound that exhibits potent and sustained PI3K inhibitory action and anti-tumor effect based thereon.